3-benzoyl-3-thiocyanatopropionic acid, alkyl esters and derivatives thereof

ABSTRACT

3-Benzoyl-3-thiocyanatopropionic acid, alkyl esters are prepared by the reaction of a 3-benzoyl-3-halopropionic acid alkyl ester with an alkali metal thiocyanate. The products so produced exhibit antitubercular activity.

United States Patent 1 Wei 1 Jan. 30, 1973 15 1 3-BENZOYL-3- THIOCYANATOPROPIONIC ACID, ALKYL ESTERS AND DERIVATIVES THEREOF [75] Inventor: Peter-H.L. Wei,Springfie1d,Pa [73] Assignee: American Home Products Corporation, New York, NY.

[22] Filed: Sept. 3, 1970 [21] App]. No.2 69,455

[52] U.S. Cl ..260/454, 424/302 FOREIGN PATENTS OR APPUCATIONS 791,291 2/1958 Great Britain ..260/454 OTHER PUBLICATIONS Luskin et al."tCarbinamines, R,R'R"'CNH2 Iv my (1956) JACS 78 pp. 4965-49671 1956).

' Tamura et a1, Bactericidal Eff. of Disinfectancts on Mycobacteria"(l961) CA 56 p. 14733 (1962), Hori et a1, Therapeutic effects of naphthoquinone ders. etc; (1961) CA 56 p. 14733 (1962).

Primary Examiner-Lewis iotts Assistant Exami nerG. Hollrah Att0rneyEdmond H. OBrien, Dwight .1. Potter, An-,

drew Kafko, Joseph M. Weigman, Vito Victor Bellino, Robert Wiser and David E. Frankhouser [57] ABSTRACT 3-Benzoy1-3-thiocyanatopropionic acid, alkyl esters are prepared by the reaction of a 3-benzoyl-3- halopropionic acidjalkyl ester with an alkali metal thiocyanate'. The products so produced exhibit antitubercular activity.

.' 9 Claims, N0 Drawings 3-BENZOYL-3-THIOCYANATOPROPIONIC ACID, ALKYL ESTERS AND DERIVATIVES THEREOF BACKGROUND OF THE INVENTION This invention relates to compositions of matter classified in the art of chemistry as S-naphthoyland 3- benzoyl-3-thiocyanatopropionic acid, alkyl esters, which possess antitubercular activity in standard biological tests.

SUMMARY OF THE INVENTION The invention sought to be patented as a composition of matter resides in the concept of a chemical compound selected from the group represented by Formula I II II YCCHCHzCOR SON wherein is a-naphthyl, B-naphthyl, or

in which R and R are either the same or different hydrogen, lower alkyl, phenyl, halogen, nitro, amino, lower alkylamino, di (lower) alkylamino, lower alkoxy, phenoxy, benzenesulfonyl, or trifluoromethyl; and R is lower alkyl.

The tangible embodiments of the compositions of the invention possess the inherent general physical properties of being crystalline solids; are substantially insoluble in water; and are soluble in organic solvents such as dimethylacetamide and benzene.

Examination of compounds produced according to the hereinafter described process reveals, upon infrared and nuclear magnetic resonance spectroscopic analysis, spectral data confirming the molecular structure hereinbefore set forth. For example, the infrared spectrum shows frequencies characteristic of the thiocyano, ester, and ketone groups. The aforementioned physical characteristic taken together with the nature of the starting materials, and the mode of synthesis,

positively confirm the structures "of the compositions TABLE A Effect against M. Tuberculosis, in vitro Strain Inhibition Concentration i -gl -l H37 Rv 0.1 3371 (Case) 0.5

Vallee M. kansasii In rats, compounds administered intraperitoneally showed no toxicity at a dose of 250 mg./kg.

The manner and process for making the invention will now be generally described to enable a person skilled in the art of chemistry to make a specific embodiment of the same as follows.

DESCRIPTION OF THE PREFERRED EMBODIMENT The compounds of the invention are prepared by treating a 3-benzoyl-3-halopropionic acid, lower alkyl ester (II) with an alkali metal thiocyanate in an unreactive polar organic solvent, preferably a lower alkanol, at a temperature of between C and C. This reaction is illustrated as follows:

For convenience, the temperature employed may be the reflux temperature of the particular solvent selected. For best results, when a lower alkanol is used as solvent, the alkyl-group of the lower alkanol should be the same as the alkyl radical of the ester moiety of the starting 3-bromo-3 benzoylpropionic acid, lower alkyl ester. The alkali metal cation of the thiocyanate compound (Ill) may be sodium, potassium or lithium,- although potassium is preferred. The halo radical of the 3-benzoyl-3-halopropionic acid, lower alkyl ester may be chloride, bromide, or iodide; however, bromide-is preferred.

3-Benzoyl-3-halopropionic acid lower alkyl ester starting materials are known compounds or may be prepared by synthetic methods well known in the art of organic chemistry. For example, a 3-benzoyl-3- halopropionic acid (lower) alkyl ester may be prepared by a three-step process which involves: (a) reacting succinic anhydride with an appropriate aryl compound under Friedel-Crafts conditions to afford a 3benzoylpropionic acid intermediate, (b) halogenating the intermediate to give a 3-halo-3-benzoylpropionic acid, and (c) esterifyi'ng the haloacid so produced. Alternatively, 3-benzoylpropionic acids may be prepared by treating an appropriate phenyl Grignard reagent with succinic anhydride. The alternate method is preferred when it is desired to prepare a 3-benzoylpropionic acid in which the phenyl moiety of the benzoyl group contains a meta-directing substituent.

3-Naphthoyl-3-halopropionic acid, lower alkyl esters maybe prepared from the appropriate naphthalene compounds by analogous procedures.

It will be apparent to one skilled in the art of organic chemistry that glutaric anhydride can be substituted for succinic anhydride in the synthesis of the starting materials hereinbefore described. The 4-benzoyl-4- koxy, and lower alkanol are meant to include branched, straight-chain and cyclic aliphatic moieties having from one'to about six carbon atoms. The term halogen as employed herein for the definition of R and R is meant to include the chlorine, bromine, fluorine, and iodine atoms.

The best mode contemplated by the inventors of carrying out their invention will now be set forth as follows:

EXAMPLE I 3-(p-Chlorobenzoyl)-3-Thiocyanatopropionic Acid, Ethyl Ester An ethanol solution of 3-bromo-3-(p-chlorobenzoyl) propionic acid, ethyl ester (12.76 g., 0.04 m) and potassium thiocyanate (3.88 g., 0.04 m) is heated to reflux for 4 hours. The reaction mixture is filtered, and the filtrate concentrated to yield a residue which is then dissolved in benzene .The benzene solution is washed with water and dried over anhydrous magnesium sulfate. After removal of benzene and treatment of the oil residue with petroleum ether, crude solid material g.) is collected. Recrystallizationfrom petroleum ether affords the title compound, m.p. 55-56C. Analysis for C H, ClNO -,S

Calculated: C, 52.42;H, 4.06; Cl, 11.91; N, 4.70; S,

10.76 Found: C, 52.23; H, 4.16; Cl, 11.91; N, 4.54; S,

10.53 [R Analysis: Spectrum (KBr) showed SC 5 N at 4.6 g., ester at 5.75 t and keto at 5.9 NMR Analysis: Spectrum (CDCl showed aromatic protons at 8 7.4 to 8.0, a methine proton at 8 4.9 to 5.2 (.multiplet), two methylene protons at 83.1 to 3.4 (two overlapping doublets) and two methylene protons at 8 4.2 (quartet) and three methyl protons at 81.25 (triplet).

Example ll 3-(p-Chlorobenzoyl)-3-Thiocyanatopropionic Acid A mixture of 3-bromo-3-( p-chlorobenzoyl)propionic acid-(8.8 g., 0.03 moles) and potassium thiocyanate (5.8 g., 0.06 moles) in aqueous dimethoxyethane is heated on a steam bath for 2 hours. Upon removal of the solvent the residual solid is collected by filtration, washed with. water, and dried at room temperature. The crude material is recrystallized from benzene to give 4.0 g. of the title compound, m.p. 171-173C. Analysis for C H ClNO S I Calculated: C, 48.98; H, 2.99; N, 5.19; S, 11.89

Found: C, 49.23; H, 3.08; N, 5.17; S, 11.65 [R Analysis: Spectrum (KBr) showed C=O at 6.0 p. at 3.4 p. and 5.85 p, and SC E N at 4.60 1.

Example I 3-(p-Chlorobenzoyl)-3-Thiocyanato-propionic Acid,

' Methyl Ester A. 3-Bromo-3-(p-chlorobenzoyl)propionic acid is dissolved in methanol, and the solution is heated at reflux temperature for 2 days. Solvent is'then removed and the resulting residue is dissolved in benzene. The benzene solution is washed with a dilute solution of sodium bicarbonate and dried over anhydrous magnesium sulfate. After filtration, the solution is concentrated to yield an oil which upon infrared analysis is shown to be 3-bromo-3-(p-chlorobenzoyl)propionic acid methyl ester. (Spectrum shows ester at 5.75 p. and keto at 5.9 u)- The methyl ester is also prepared by treating 3- brom0-3-(p-chlorobenzoyl)propionic acid with diazomethane following the procedure described in Org. Syn., Coll. Vol. ll, p. 165. The infrared spectrum of the product is identical to that obtained by esterification with methanol. a

B. A methanol solution of 3-bromo-3-(pchlorobenzoyl) propionic acid, methyl ester (9.15 g., 0.03 mole) and potassium thiocyanate (3.0 g., 0.03 mole) is heated at reflux temperature for 2% hours. The reaction mixture is filtered and the filtrateconcentrated. The residue is dissolved in benzene. The benzene solution is then washed with water and dried over anhydrous magnesium sulfate. After'filtration,the solution is concentrated'to yield a residue which is washed with petroleum ether. Upon drying, the crude material weighs 8.5 g. Recrystallization from cyclohexane, affords the title compound, m.p. -76C. Analysis for C, H ,CINO S Calculated: C, 50.79; H, 3.55; N, 4.94; CI, 12.49; S,

Found: C, 50.90; H, 3.55; N, 4.85; CI, 12.36; S,

lR Analysis: Spectrum showed SC 'N at 4.65 p. ester at 5.75 t, and keto at 5.95 p..

NMR Analysis: Spectrum (CDCI showed four aromatic protons at 87.85 (quartet), one methine proton at 85.10 (overlapping doublets), three methoxy protons at 83.78, and two methylene protons at 83.32 (over-lapping doublets).

, Example lV 3-Benzoyl-3-Thiocyanatopropionic Acid, Methyl Ester Example V 3-Thiocyanato-3-(a,a,a-Trifluoro-p-Toluoyl) Propionic Acid, Ethyl Ester An ethanol solution of 3-bromo-3-(a,a,a-trifluoro-ptoluoyl)propionic acid, ethyl ester (7.1 g., 0.02 m) and potassium thiocyanate (1.9 g., 0.02 m) is heated to reflux for 2 hours. The reaction mixture is then filtered,

and the filtrate concentrated. The residue is dissolved I in benzene. The benzene solution is then washed with water and dried over anhydrous magnesium sulfate. After filtration, the solution is concentrated to yield a residue which upon crystallization from petroleum ether affords 1.0 g. of the title compound, m.p. 68-69 C. Analysis for C H F NO S Calculated: C, 50.76; H, 3.65; N, 4.23; S, 9.68 Found: C, 50.42; H, 3.88; N, 4.43; S, 9.54 IR Analysis Spectrum (KBr) showed SC N at 4.6 p., ester at 5.75 [1,, and keto at 5.85 ;1.. NMR Analysis: Spectrum (CDCl showed three ethoxy methyl protons at 81.27 (triplet), two methylene protons at 83.32 (over-lapping doublet), two ethoxy methylene protons at 84.22 (quartet), and one methine at 85.10 and four aromatic protons at 88.09.

Example Vl 3-(4-Biphenylylcarbonyl)-3-Bromopropionic Acid, Ethyl Ester To a chloroform solution of 3-(4-biphenylylcarbonyl) propionic acid, ethyl ester (5.6 g., 0.02 m) two drops of bromine is added. The solution is warmed until the color is discharged. Then the remainder of the bromine (3.2 g., 0.02 m) is gradually added and the solution is heated to reflux for 1 hour. The solution is filtered and solvent removed. The oily residue upon treatment with petroleum ethergives 7.0 g. of crude solid material, which upon recrystallization from cyclohexane yields the title compound, m.p. 80-8 1C. Analysis for C H BrO Calculated: C, 59.85; H, 4.75; Br, 22.13

Found: C, 59.63; H, 4.72; Br, 22.00

lR Analysis: Spectrum (KBr) showed ester at 5.7 p. and keto at 5.9 p.. NMR Analysis: Spectrum (CDCl showed nine aromatic protons at 87.95, two ethoxy methylene protons at 84.28, two methylene protons at 83.40, and three ethoxy methyl protons at 81.28.

Example Vll 3-(4-Biphenylylcarbonyl )-3-Thiocyanatopropionic Acid, Ethyl Ester An ethanol solution of 3-bromo-3-(4-biphenylylcarbonyl)propionic acid, ethyl ester (3.6 g., 0.01 m) and potassium thiocyanate (1.1 g., 0.012 m) is heated to reflux for 2% hours. After filtration, the solvent is removed. The residual oil is dissolved in benzene and the benzene solution is first washed with water and then dried over anhydrous magnesium sulfate. Removal of benzene affords a residual oil that solidifies upon treatment with petroleum ether. Recrystallization from cyclohexane gives 2.5 of the title compound, m.p. l07-109C.

Analysis for C,,,H -,NO S

Calculated: C, 67.23; H, 5.05; N, 4.13; S, 9.45

Found: C, 67.22; H, 5.22; N, 4.11; S, 9.31 IR Analysis: Spectrum (KBr) showed SC 5 N at 4.6 p, ester at 5.75 g., and keto at 5.95 p. NMR Analysis: Spectrum (CDCl showed nine aromatic protons at 87.95 (multiplet), one methine proton at 85.24 (triplet), two ethoxy methylene protons at 84.28 (quarter), two methylene protons at 83.35 (overlapping quartets), and three ethoxy methyl protons at O 81.30 (triplet).

Example VIIl 3-Bromo-3-(p-Fluorobenzoyl) Propionic Acid, Ethyl Ester To a boiling chloroform solution of 3-(pfluorobenzoyl) propionic acid, ethyl ester (8.7 g.) is gradually added bromine (6.2 g.). The solution is heated to reflux temperature for one half hour. Solvent is then removed, the residue is recrystallized from petroleum ether to yield 6.8 g. of the title compound, m.p. 3233C. Analysis for C N' BrFQ,

Calculated: C, 47.55; H, 3.99; Br, 26.37

Found: C, 47.96; H, 3.96; Br, 26.60 [R Analysis: Spectrum (KBr) showed ester at 5.8 p. and keto at 5.9 p. NMR Analysis: Spectrum (CDCl showed three ethoxy methyl protons at 81.22 (triplet), two methylene protons at 83.28 (two sets of quartets), two ethoxy methylene protons at 84.20 (quartet), one methine proton at 85.53 (over-lapping doublets), and four aromatic protons at 87.70 (multiplet).

Example IX 3-(p-Fluorobenzoyl)-3-Thiocyanatopropionic Acid, Ethyl Ester Following the procedure described in Example I, but substituting an equivalent amount of 3-bromo-3-(pfluorobenzoyl) propionic acid, ethyl ester for 3-bromo- 3-(p-chlorobenzoyl) propionic acid, ethyl esterthere is obtained the title product.

Example X Following the procedure of Example I, but substituting equivalent amounts of the appropriate substituted 3-halo-3-benzoylpropionic acid, lower alkyl esters for 3-bromo-3-(p-chlorobenzoyl)propionic acid, lower alkyl ester, and also substituting an appropriate lower alkanol for ethanol, there is obtained the products shown in Table A.

Substituted 3-Halo-3- Product Benzoylpropionic Acid, Lower Alkyl Ester 3-bromo-3-(p-iodobenzoyl) 3-(p-iodobenzoyl)-3-thiopropionic acid, methyl ester cyanatopropionic acid, methyl ester 3-(p-nitrobenzoyl)-3- 3'iodo-3-( p-nitrobenzoyl) thiocyanatopropionic acid,

3-bromo-3-(p-tert-butoxy benzoyl)propionic acid, propyl ester 3-bromo-3-[p-(n-hexyl)benzoyl] propionic acid. methyl ester 3-chloro-3-(2,4-dimethoxybenzoynpropionic acid, lsopropy ester 3-bromo-3-(3-biphenylylcarbonyl)propionic acid,

n-hexyl ester 3-bromo-3-( 2-methyl-4 phenoxybenzoyl )propionic acid, et yl ester 3-bromo-3-[(p-benzenesulfonyl) benzoyllproptonic acid, methyl ester 3-bromo-3-[4-propoxy-2-(hexylamino)benzoyl]propionic acid, n-butyl ester 3-bromo-3-(2,6-diaminobenzoyl) propionic acid, propyl ester 3-bromo-3-[p-( tt-butylamiho) benzoyllpropionic acid, ethyl ester 3-bromo-3-(2-methyl-4-pentyloxybenzoyl)propionic acid, n-pentyl ester 3-bromo-[p-(iso butylamino) benzoyl1propionic acid, ethyl ester 3-brom0-3-(2-chloro4-isopropylbenzoyl)propionic acid, isobutyl ester 3-bromo-3-(m-nitrobenzoyl) propionic acid, n-hexyl ester 3-bromo-3-(2-nitro-4-ethyl- 1 benzoyl)propionic acid, ethyl ester 3-bromo-3-[p-( N,N-dihexylamino) benzoyl1propionic acid, ethyl ester 3-bromo-3-mesitoylpropionic acid, methyl ester 3-bromo-3-(3-chloro-4-cyclohexylbenzoyl)propionic acid, methyl ester 3-bromo-3-(2,4-dimethylbenzoyl) propionic acid,'ethyl ester acid, n-hexyl ester 3-(2-methyl-4-phenoxybenzoyl)3-thiocyanatopropionic acid, ethyl ester 3-[(p -benzenesulfonyl) benzoyll-B-thiocyanatopropionic acid, methyl ester 3-(4-propoxy-2-hexylaminob'enzoyl)propionic acid, n-butyl ester 3-(2,6-diaminobenzoyl) -3-thiocyanatopropionic acid, propyl ester benzoyl ]-3-thiocyanatopropionic acid, ethyl ester 3-(3-amino-4-bromobenzoyl) -3-thiocyanatopropionic acid, ethyl ester 3-[p-(N,N-diethylamino) benzoyl lit-thiocyanatopropionic acid, methyl ester 3-(2-methyl-4-pentyloxybenzoyl)-3-thiocyanatopropionic acid,,n-pentyl ester 3-[ (p-isobutylamino) benzoyl1-3-thiocyanatopropionic acid, ethyl ester 3-(2-chloro4-isopropylbenzoyl)-3-thiocyanatopropionic acid, isobutyl ester 3-(m-nitrobenzoyl-S-thiocyanatopropionic acid, n-hexyl ester 3-(2-nitro-4-ethylbenzoyl) -3-thiocyanatopropionic acid, ethyl ester 3[p-(N,N-dihexylamino) benzoyl1-3-thiocyanatopropionic acid, ethyl ester 3-mesitoyl-S-thiocyanatopropionic acid, methyl ester 3-(3-chloro-4-cyclohexylbenzoyl )S-thiocyanatopropionic acid, methyl ester 3-(2,4-dimethylbenzoyl) 3-thiocyanato propionic acid, ethyl ester Example Xl Following the procedure of Example 3B but substituting an equivalent amount of 3-bromo-3-(anaphthoyl)propionic acid methyl ester for 3-bromo-3- (p-chlorobenzoyl)propionic acid, methyl ester, there is obtained the title compound.

ln like manner, there is obtained 3-(B-naphthoyl)-3- thiocyanatopropionic acid methyl ester.

The subject matter which the applicants regard as their invention is particularly pointed out and distinctly claimed as follows:

1. A compound selected from the group consisting of those having the structure wherein Y is a-naphthyl, B-naphthyl, or

inwhich R and R are, either the same or different, hydrogen, lower alkyl, phenyl, halogen, nitro, amino, lower alkyl amino, di (lower) alkyl amino,lower alkoxy, phenoxy, benzenesulfonyl, or trifluoromethyl; and R is lower alkyl.

2. A compound as described in claim 1 which is: 3- (p-chlorobenzoyl)-3-thiocyanatopropionic acid, ethyl ester.

3. A compound as described in claim 1 which is: 3- (p-chlorobenzoyl)-3-thiocyanatopropionic acid, methyl ester.

4. A compound as described in claim 1 which is: 3- benzoyI-B-thiocyanatopropionic acid, methyl ester.

5. A compound as described in claim 1 which is: 3- thio-cyanato-3-(a,a,a-trifluoro-p-toluoyl)propionic acid, ethyl ester.

6. A compound as described in claim 1 which is: 3- (4-biphenylylcarbonyl)-3-thiocyanatopropionic acid, ethyl ester.

7. A compound as described in claim 1 which is: 3- (p-fluorobenzoyl)-3-thiocyanatopropionic acid, ethyl ester.

' 8., A compound as described in claim 1 which is: 3- (a-naphthoyl)-3-thiocyanatopropionic acid, methyl ester.

9. A compound as described in claim 1 which is: 3- (B-naphthoyl)-3-thiocyanatopropionic acid, methyl ester. 

1. A compound selected from the group consisting of those having the structure wherein Y is Alpha -naphthyl, Beta -naphthyl, or in which R1 and R2 are, either the same or different, hydrogen, lower alkyl, phenyl, halogen, nitro, amino, lower alkyl amino, di (lower) alkyl amino, lower alkoxy, phenoxy, benzenesulfonyl, or trifluoromethyl; and R is lower alkyl.
 2. A compound as described in claim 1 which is: 3-(p-chlorobenzoyl)-3-thiocyanatopropionic acid, ethyl ester.
 3. A compound as described in claim 1 which is: 3-(p-chlorobenzoyl)-3-thiocyanatopropionic acid, methyl ester.
 4. A compound as described in claim 1 which is: 3-benzoyl-3-thiocyanatopropionic acid, methyl ester.
 5. A compound as described in claim 1 which is: 3-thio-cyanato-3-( Alpha , Alpha , Alpha -trifluoro-p-toluoyl)propionic acid, ethyl ester.
 6. A compound as described in claim 1 which is: 3-(4-biphenylylcarbonyl)-3-thiocyanatopropionic acid, ethyl ester.
 7. A compound as described in claim 1 which is: 3-(p-fluorobenzoyl)-3-thiocyanatopropionic acid, ethyl ester.
 8. A compound as described in claim 1 which is: 3-( Alpha -naphthoyl)-3-thiocyanatopropionic acid, methyl ester. 